UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to compare the resistance pattern to zidovudine plus lamivudine in zidovudine-experienced patients, we studied three HIV-1-infected patients enrolled in NUCB3004, an open-label trial. Over a 24-week follow-up, the patients were studied for drug sensitivity, reverse transcriptase genotype, viral load (HIV-1 RNA level) and viral phenotype (syncytium inducing (SI) or non-syncytium inducing). Virus isolates derived from peripheral blood mononuclear cells (PBMCs) were tested for changes in drug susceptibility. Proviral DNA in the patients' PBMCs and RNA from plasma and culture supernatant were subjected to amplification and sequencing. All three HIV-1 strains showed a decreased susceptibility to either zidovudine or lamivudine after 24 weeks of therapy. The pattern of DNA genotypic resistance to lamivudine in patient A showed a mutation at codon 184 of the reverse transcriptase-encoding gene (methionine to valine). No HIV-1 strains with lamivudine-related mutations in proviral DNA were found among the isolates obtained from patients B and C. In these two patients, the mutation at codon 184 of the reverse transcriptase-encoding gene appeared in RNA, both in plasma and in culture supernatant. Viral phenotyping revealed the maintenance of the SI phenotype at week 24. Two out of the three patients experienced a reduction in HIV-1 RNA levels after 24 weeks of therapy, and in two out of three there was a rebound in viral load at week 28 together with the onset of the codon 184 mutation in RNA. The degree of phenotypic resistance to both zidovudine and lamivudine correlated with the amino acid changes in RNA and the rapid increase in viral load.
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PMID:Loss of antiviral effect owing to zidovudine and lamivudine double resistance in HIV-1-infected patients in an ongoing open-label trial. 1132 65

When human immunodeficiency virus type 1 (HIV-1) is selected for resistance to 3TC, the methionine normally present at position 184 is replaced by valine or isoleucine. Position 184 is the X of the conserved YXDD motif; positions 185 and 186 form part of the triad of aspartic acids at the polymerase active site. Structural and biochemical analysis of 3TC-resistant HIV-1 reverse transcriptase (RT) led to a model in which a beta-branched amino acid at position 184 would act as a steric gate. Normal deoxynucleoside triphosphates (dNTPs) could still be incorporated; the oxathiolane ring of 3TCTP would clash with the beta branch of the amino acid at position 184. This model can also explain 3TC resistance in feline immunodeficiency virus and human hepatitis B virus. However, it has been reported (14) that murine leukemia viruses (MLVs) with valine (the amino acid present in the wild type), isoleucine, alanine, serine, or methionine at the X position of the YXDD motif are all resistant to 3TC. We prepared purified wild-type MLV RT and mutant MLV RTs with methionine, isoleucine, and alanine at the X position. The behavior of these RTs was compared to those of wild-type HIV-1 RT and of HIV-1 RT with alanine at the X position. If alanine is present at the X position, both MLV RT and HIV-1 RT are relatively resistant to 3TCTP in vitro. However, the mutant enzymes were impaired relative to their wild-type counterparts; there appears to be steric hindrance for both 3TCTP and normal dNTPs.
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PMID:YADD mutants of human immunodeficiency virus type 1 and Moloney murine leukemia virus reverse transcriptase are resistant to lamivudine triphosphate (3TCTP) in vitro. 1141 98

Resistance to human immunodeficiency virus type 1 protease (HIV PR) inhibitors results primarily from the selection of multiple mutations in the protease region. Because many of these mutations are selected for the ability to decrease inhibitor binding in the active site, they also affect substrate binding and potentially substrate specificity. This work investigates the substrate specificity of a panel of clinically derived protease inhibitor-resistant HIV PR variants. To compare protease specificity, we have used positional-scanning, synthetic combinatorial peptide libraries as well as a select number of individual substrates. The subsite preferences of wild-type HIV PR determined by using the substrate libraries are consistent with prior reports, validating the use of these libraries to compare specificity among a panel of HIV PR variants. Five out of seven protease variants demonstrated subtle differences in specificity that may have significant impacts on their abilities to function in viral maturation. Of these, four variants demonstrated up to fourfold changes in the preference for valine relative to alanine at position P2 when tested on individual peptide substrates. This change correlated with a common mutation in the viral NC/p1 cleavage site. These mutations may represent a mechanism by which severely compromised, drug-resistant viral strains can increase fitness levels. Understanding the altered substrate specificity of drug-resistant HIV PR should be valuable in the design of future generations of protease inhibitors as well as in elucidating the molecular basis of regulation of proteolysis in HIV.
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PMID:Altered substrate specificity of drug-resistant human immunodeficiency virus type 1 protease. 1177 10

Abacavir (1592U89, or Ziagen) is a powerful and selective inhibitor of HIV-1 viral replication that has been approved by the FDA for treatment of acquired immunodeficiency syndrome. Abacavir is metabolized to the active compound carbovir triphosphate (CBVTP). This compound is a guanosine analogue containing a 2',3'-unsaturation in its planar carbocyclic deoxyribose ring that acts on HIV-1 reverse transcriptase (RT(WT)) as a molecular target, resulting in chain termination of DNA synthesis. A single amino acid change from methionine 184 to valine in HIV-1 RT (RT(M184V)) has been observed clinically in response to abacavir treatment. The ability of the natural substrate, dGTP, or CBVTP to be utilized during DNA- and RNA-directed polymerization by RT(WT) and RT(M184V) was defined by pre-steady-state kinetic parameters. In the case of RT(WT), CBVTP was found to be a surprisingly poor substrate relative to dGTP. In both DNA- and RNA-directed polymerization, a decrease in the efficiency of CBVTP utilization with respect to dGTP was found with RT(M184V), suggesting that this mutation confers resistance at the level of CBVMP incorporation. The relatively low incorporation efficiency for RT(WT) was unanticipated considering earlier studies showing that the triphosphate form of a thymidine nucleoside analogue containing a planar 2',3'-unsaturated ribose ring, D4TTP, was incorporated with high efficiency relative to the natural substrate, dTTP. The difference may be related to the isosteric replacement of oxygen in the deoxyribose ring with carbon. This hypothesis was tested by synthesizing and evaluating D4GTP (the planar 2',3'-unsaturated deoxyribose guanosine analogue that is complementary to D4TTP). In contrast to CBVTP, D4GTP was found to be an excellent substrate for RT(WT) and no resistance was conferred by the M184V mutation, thus providing novel insight into structure-activity relationships for nucleoside-based inhibitors. In this work, we illustrate how an understanding of the molecular mechanism of inhibition and drug resistance led to the discovery of a novel prodrug of D4G. This compound shows promise as a potent antiviral especially with the drug resistant M184V HIV-1 RT that is so often encountered in a clinical setting.
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PMID:Insights into the molecular mechanism of inhibition and drug resistance for HIV-1 RT with carbovir triphosphate. 1195 63

An efficient, short synthesis of four potential prodrugs of 3'-azido-3'-deoxythymidine (AZT) and their antibacterial activity are reported. The 5'-OH group of AZT was functionalized with oxalyl chloride obtaining an acyl chloride derivative (AZT-Ox), which by further transformation with leucine, isoleucine and valine amino acids led to the corresponding AZT analogs, namely AZT-Leu, AZT-iLeu and AZT-Val. A carboxyl acid derivative (AZT-Ac) was also obtained by hydrolysis of AZT-Ox. These compounds, which exhibit anti HIV activity, have killed collection and clinical strains of some opportunistic infectious agents in AIDS-related complex. Thus, the clinical strains, K. oxytoca, S. typhi and K. pneumoniae, and collection strain K. pneumoniae ATCC 10031 showed sensitivity to antibiotics. The activity order for the studied compounds against the most sensitive strain (K. pneumoniae ATCC 10031) was AZT-Leu > AZT-iLeu > AZT-Val > AZT-Ac > AZT. On the other hand, the activity order for the second most sensitive strain (K. oxytoca) was AZT-Leu > AZT-Val = AZT-Ac > AZT-iLeu > AZT. The most effective antibacterial drug AZT-Leu, M.I.C.=0.125 microgmL(-1)) was 16 times more active than AZT (AZT, M.I.C.=2 microg mL(-1)) against K.
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PMID:Synthesis and in vitro antibacterial activity of novel 5'-O-analog derivatives of zidovudine as potential prodrugs. 1199 Nov 64

Drug-resistant mutants with a methionine-to-valine substitution at position 184 of reverse transcriptase (M184V) emerged within 5 weeks of initiation of therapy in four newborn macaques infected with simian immunodeficiency virus (SIVmac251) and treated with lamivudine (3TC) or emtricitabine [(-)-FTC] (two animals per drug). Thus, this animal model mimics the rapid emergence of M184V mutants of HIV-1 during 3TC therapy of human patients. One animal of each treatment group developed fatal immunodeficiency at 12 weeks of age, which is similar to the rapid disease course seen in most untreated SIVmac251-infected infant macaques. To further evaluate the effect of the M184V mutation on viral fitness and virulence, groups of juvenile macaques were inoculated with the molecular clone SIVmac239 with either the wild-type sequence (group A [n = 5]) or the M184V sequence (SIVmac239-184V; group B [n = 5] and group C [n = 2]). The two SIVmac239-184V-infected animals of group C did not receive any drug treatment, and in both animals the virus population reverted to predominantly wild type (184M) by 8 weeks after inoculation. The other five SIVmac239-184V-infected animals (group B) were treated with (-)-FTC to prevent reversion. Although virus levels 1 week after inoculation were lower in the SIVmac239-184V-infected macaques than in the SIVmac239-infected animals, no significant differences were observed from week 2 onwards. Two animals in each group developed AIDS and were euthanized, while all other animals were clinically stable at 46 weeks of infection. These data demonstrate that the M184V mutation in SIV conferred a slightly reduced fitness but did not affect disease outcome.
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PMID:Virulence and reduced fitness of simian immunodeficiency virus with the M184V mutation in reverse transcriptase. 1202 41

Both the beta-D-(+) and beta-L-(-)-enantiomers of 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (D4FC) are clinically relevant compounds because of their potent anti-HIV and anti-HBV activities. Cross-resistance to L-D4FC with HBV containing a mutation in the conserved polymerase YMDD region has been observed. In order to better understand the effects of stereochemistry on planar 5-fluorinated cytidine analogs and to gain insight into resistance caused by YMDD mutations in HIV-1 reverse transcriptase (RT), a combination of transient kinetic studies and computer modeling were employed. In contrast to studies with the (+) and (-) isomers of 3TC-TP and FTC-TP, it was found that wild type RT had a high enantiomeric selectivity between the D-(+) and L-(-) isomers of D4FC-TP. While no resistance was conferred by the methionine 184 to valine mutation to D-D4FC-TP, L-D4FC-TP was incorporated 50- to 70-fold less efficiently. The kinetic parameters of incorporation in the presence of L-D4FC-TP by RT(WT) and the mechanism of resistance by RT(M184V) were found to be distinct from those seen with the corresponding L-isomers containing an oxathiolane ring: (-)-3TC-TP and (-)-FTC-TP. Molecular modeling suggests that L- and D-D4FC-TP are positioned in the active site favorably for incorporation by RT(WT) and that L-D4FC-TP, but not D-D4FC-TP, is sterically hindered by the addition of a beta branched amino acid at position 184 of RT(M184V).
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PMID:Interactions of enantiomers of 2',3'-didehydro-2',3'-dideoxy-fluorocytidine with wild type and M184V mutant HIV-1 reverse transcriptase. 1240 4

Human immunodeficiency virus type 1 (HIV-1) can infect nondividing cells productively because the nuclear import of viral nucleic acids occurs in the absence of cell division. A number of viral factors that are present in HIV-1 preintegration complexes (PICs) have been assigned functions in nuclear import, including an essential valine at position 165 in integrase (IN-V165) and the central polypurine tract (cPPT). In this article, we report a comparison of the replication and infection characteristics of viruses with disruptions in the cPPT and IN-V165. We found that viruses with cPPT mutations still replicated productively in both dividing and nondividing cells, while viruses with a mutation at IN-V165 did not. Direct observation of the subcellular localization of HIV-1 cDNAs by fluorescence in situ hybridization revealed that cDNAs synthesized by both mutant viruses were readily detected in the nucleus. Thus, neither the cPPT nor the valine residue at position 165 of integrase is essential for the nuclear import of HIV-1 PICs.
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PMID:Reassessment of the roles of integrase and the central DNA flap in human immunodeficiency virus type 1 nuclear import. 1241 50

The methionine-to-valine mutation in codon 184 (M184V) in reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) or simian immunodeficiency virus (SIV) confers resistance to (-)-2'-deoxy-3'-thiacytidine (3TC; lamivudine) and increased sensitivity to 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir). We have used the SIV model to evaluate the effect of the M184V mutation on the emergence of resistance to the combination of 3TC plus PMPA. A site-directed mutant of SIVmac239 containing M184V (SIVmac239-184V) was used to select for resistance to both 3TC and PMPA by serial passage in the presence of increasing concentrations of both drugs. Under these selection conditions, the M184V mutation reverted in the majority of the selections. Variants resistant to both drugs were found to have the lysine-to-arginine mutation at codon 65 (K65R), which has previously been associated with resistance to PMPA in both SIV and HIV. Similarly, in rhesus macaques infected with SIVmac239-184V for 46 weeks and treated daily with (-)-2'-deoxy-5-fluoro-3'-thiacytidine [(-)-FTC], there was no reversion of M184V, but this mutation reverted to 184 M in all three animals within 24 weeks of treatment with (-)-FTC and PMPA. Although the addition of PMPA to the (-)-FTC therapy induced a decrease in virus loads in plasma, these loads eventually returned to pre-PMPA levels in each case. All animals receiving this combination developed the K65R mutation. These results demonstrate that the combination of PMPA with 3TC or (-)-FTC selects for the K65R mutation and against the M184V mutation in SIV RT.
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PMID:Reversion of the M184V mutation in simian immunodeficiency virus reverse transcriptase is selected by tenofovir, even in the presence of lamivudine. 1250 28

We have examined the effect of a medroxyprogesterone therapy in HIV-infected patients under appropriate nutrition for anabolism. The experiments were performed on 12 men (mean age 40 y), HIV seropositive but free of any clinically active opportunistic infection for at least one month. The patients underwent a 2-week baseline diet period (1.2 g protein x kg(-1) body weight (BW) x d(-1)) and then a 5-week experimental period with again the baseline diet in conjunction with supplements including Tonexis HP (0.7 g protein x kg(-1) BW) x d(-1)), L-threonine (0.018 g x kg(-1) BW x d(-1)) and L-methionine (0.013 g x kg(-1) BW x d(-1)). Indeed HIV-infected patients showed deficiencies in these amino acids. They were randomly divided into groups I and II under double-blinded condition. Group II was given medroxyprogesterone acetate (0.4 g x d(-1)) during the last 3 weeks whereas group I received a placebo. All the patients significantly increased their body weight (P < 0.05) during the experimental periods. Those under medroxyprogesterone tended to show a higher but not significant weight gain (+3.1 +/- 1.0 kg in group II and +1.9 +/- 0.3 kg in group I). Blood free amino acids were used as rough indicators of amino acid utilization and were analyzed prior and during acute 150 min intravenous infusion of a complete glucose-amino acid mixture. This test was done before and at the end of the experimental periods. Basal essential blood free amino acids were similar in the two groups and did not change during the experimental period. Most essential amino acids increased following glucose-amino acid infusions. The incremental increase was of less magnitude after the experimental period than before when medroxyprogesterone was present (P < 0.05 for valine, leucine, lysine, threonine and methionine). This was not the case in the absence of the hormone. We concluded that medroxyprogesterone might improve the efficacy of an oral protein-rich nutritional support in HIV-infected patients.
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PMID:Effect of medroxyprogesterone acetate on the efficiency of an oral protein-rich nutritional support in HIV-infected patients. 1295 19

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